Monday, November 29, 2021

Are you on clenbuterol? (3)

More from Risérus

Trans fatty acids and insulin resistance

"This is especially true [inducing insulin resistance] for conjugated TFA, i.e. conjugated linoleic acid (CLA), which clearly impairs insulin sensitivity."

I think is reasonable to assume that Risérus expects ordinary trans fatty acids to impair insulin sensitivity too, though not quite as effectively as CLA does. He just needs a big enough intervention study to prove it.

Of course he is wrong in this. He's also correct.

There is a saying that the dose makes the poison. CLA warrants a post or two on its own but it's enough to say for now that there is a toxicity syndrome, reliably induced in rodents, because it's ability to induce lipolysis can be frankly too effective. Including death of adipocytes.

Trans fatty acids are the little brother to CLA as far as lipolysis is concerned.

From the Protons point of view oxidising fats, any fats, will be better than glucose, even with insulin, at inducing reverse electron transport through complex I.

Weight loss, ie fat loss, necessitates the oxidation of lost fat. The better the lipolytic agent, the more fat to oxidise and the more insulin resistance.

Extended fasting is classically a state of profoundly increased fatty acid release from adipocytes and the oxidation of those fatty acids, with insulin resistance being intrinsic to this state. And essential for survival. Protons.

So it is impossible to lose fat without the development of some degree of fat oxidation induced insulin resistance.

CLA is good at lipolysis, trans fats less so but still better than a poke in the eye with a sharp stick.

The thought train which goes on from here is that lipolytic agents should acutely reduce insulin sensitivity directly related to the degree of fat loss. In the long term a lipolytic agent which enforces sustained fat loss will provide the low rate of basal lipolysis intrinsic to small adipocytes and so increase insulin sensitivity, especially if the lipolytic agent is not currently active.

I'm going to talk about clenbuterol next but the other agent of interest is metformin. From the Protons view metformin simply blocks the glycerophosphate shuttle, drops the FADH2 input to the electron transport chain so blunts insulin signalling which needs some degree of ROS generation to happen. Blunting insulin signalling allows lipolysis and suppresses hunger in proportion to these fat loss calories. Once adipocytes are small enough from this blunted insulin signalling we are back in to small adipocytes with low basal lipolysis so increased insulin sensitivity, especially if the metformin has worn off... In humans metformin takes a few weeks to "work". I doubt the degree of fat loss needs to be gross, just enough to reduce basal lipolysis a little.

Back to clenbuterol. Calves this time (at least it's not Bl/6 mice!).

Clenbuterol-Induced Insulin Resistance in Calves Measured by Hyperinsulinemic, Euglycemic Clamp Technique

Basically it's looking at acute treatment with a lipolytic agent. Here are the glucose infusion rates under an hyperinsulinaemic clamp:

The black squares are the infusion rates after clenbuterol, the open squares before injection. 

It's clear from the bottom graph, while the drug is active, that the treated  calves are insulin resistant, requiring significantly less glucose during the hyperinsulinaemic clamp compared to before treatment.

The upper graph shows no effect if you wait 16-25 hours before the clamp, ie until the clenbuterol has worn off. Interestingly the square colours are reversed in this upper graph. Even if the rates are ns different, we still have the calves showing as more insulin sensitive in the aftermath of a period of lipolysis. You can't force lipolysis without shrinking adipocytes. Shrunken adipocytes will always have lower basal lipolysis compared to larger adipocytes. This should show as less insulin resistance. There is a suggestion of that here.

Here are the results tabulated

I was going to go on to talk about chronic clenbuterol and the enhanced insulin sensitivity it provides. Undoubtedly chronic, high dose clenbuterol induces low adipocyte size, muscle hypertrophy and markedly improved insulin sensitivity. But the mechanism becomes complex and convoluted. I spent a little time on this fascinating paper which is comprehensible from the Protons point of view but horribly convoluted by beta receptor down regulation leading to blunted adrenaline signalling. Which affects insulin sensitivity directly.

Clenbuterol prevents epinephrine from antagonizing insulin-stimulated muscle glucose uptake

Fascinating but I'll leave that can of worms alone. It does leave me wondering a little about the acute effects of clenbuterol on fully active beta receptors and their interaction with insulin signalling. Messy. I'll leave the above post unchanged but bear in mind a lot is going on when you take an adrenergic agonist drug, in addition to lipolysis!



Jay said...

I'd best rethink having a T-shirt made with "Death to All Adipocytes" emblazoned across my chest. Your blog regarding clenbuterol has my mind going in several directions - as usual. I am deeply suspicious that you intend such outcomes. Your comments on CLA caught my eye and appear to be a teaser for a future blog(s). Besides the obvious: Is there a safe dose of CLA, and how would that be determined? I am also curious to know if you will have thoughts as to whether CLA consumption lowers cholesterol(s)? I will not muddy the water by asking if that is a good thing or not.

Passthecream said...

The time lag of Metformin --- I remember when I started taking this about 26 years ago that I was disappointed that the blood sugar lowering took a long time to kick in. I should have adjusted my diet, it would have been much faster to low carb but I was in a state of ignorance and eating lots of 'heart healthy' stuff. However the lower gastro intestinal effects kicked in pretty quickly. Only a day or two.

"Extended fasting is classically a state of profoundly increased fatty acid release from adipocytes and the oxidation of those fatty acids, with insulin resistance being intrinsic to this state"

There's some interesting type of symmetry there in that this aspect of fasting resembles the outcome of bloated overloaded adipocytes which just can't help but to catastrophically release FFAs with accompanying insulin resistance. Is this the nexus between functional insulin resistance and pathological? Maybe i.r. is always the right outcome in these different degrees? ---- gotta get those calories out of there, can't lock them away!

I wonder if beta oxidation chews through ( hydrogenated) trans fats as though they were regular saturated fats such as palmitate?

Passthecream said...

... 16 years ...

raphi said...

I grew up with asthma and so used quite a bit of salbutamol. I didn't know that it (and clenbuterol) were considered doping substances!

Makes sense it helped with asthma given its b2 adrenergic agonism... pity no one told me when I was a kid that you could achieve equivalent if not bigger discharges of norepinephrine via hypercapnia hyperventilation - which also avoids the receptor desensitisation that occurs with chronic use for symptomatic treatment of asthma. I "felt" that effect in large part by feeling extremely groggy in the morning. of course, the antihistamines taken before bed time mustn't have helped either...

raphi said...

*hypercapniC !

Rutger said...

@raphi, there's quite some "cynicism" around exercise-induced astma in professional sports. Similar to the popular clenbuterol tainted steaks.

If you want to have a laugh, search for something like "Froome chased by giant inhaler" which should bring up some images from the legendary stage 19 of the Giro in 2018.

Passthecream said...

Seeking answers to my beta oxidation question, this is interesting

So it looks like a yes, then a no, for that specific tfa.

karl said...

I'm reading JFK-jr's book - on "Worth the risk"-Fauci. Amazing..

I didn't know that he was involved so heavily in twisting the AIDs research - to the point that much of what I thought I knew about AIDs was mostly Fauci's propaganda intended to sell drugs. If even half of the issues are real we have a huge problem. There is a geriatric madman leading the worlds response to CoVid.

Some tidbits from the book:
These agencies hold patents - and somehow Fauci holds some of the patents. Public money that develops technology should actually belong to the people - not to bureaucrats. The regulator capture comes from both sides - both are profiting. This is just wrong.

I thought things were corrupt - I was wrong - corrupt isn't close to a strong enough word.

Fauci’s wife(Christine Grady) is in charge of bioethics at NIH. This is sad because informed consent is what they are supposed to protect - and missing with these EUA Vaccines and much of drug research.

The biggest health issue is the T2D/obesity pandemic - the agency that Fauci rigidly controls using tactics of a tyrant should actually be funding research to understand this problem - not just to develop patentable drugs.

I didn't realize that children are now getting roughly 60 vaccinations - for all sorts of things. The older vaccines seem to be low risk - but I don't think children today are better off getting exposed to risks that don't tally with the low risks of most of these diseases.

This is a hard book to read - it is quite depressing - but I think it is important for people to read it.

It told about some children that were forced to be compliant for some drug research - first with NG tubes - later with a tube directly to the stomach.

My idea that the abuses of medical ethics were a thing of the past was naive - It seems not only did they abuse children in the USA - but even worse things to children overseas where they could get away more. Gates is in close regular contact with Fauci - I thought Gates was a sociopath from my work in electronics - birds of a feather..

I did a lot of digging to figure out why everything about CoVid seemed bonkers - I think I get it now - seriously depressing - this book filled in some of the blanks. Could be we are entering a new dark-age, where evil people run the world.

Are some of the things in the book overstated? Could be - but the only defense I've heard is ad hominid attacks - which makes me believe the book.

Passthecream said...

Karl, do you mean RFK-jr " The real Anthony Fauci"?

cavenewt said...

karl—I bought RFK Jr's book about Fauci and Gates, and will be starting it tomorrow (the Kindle version for instant gratification). Chris Masterjohn has a thorough summary, so for those who don't want to tackle a whole book this will give you more than a flavor.

If only 50% of this is true it turns out that I've been not nearly cynical enough.

Passthecream said...

CN "If only 50% of this is true it turns out that I've been not nearly cynical enough."

I find it pays to be at least 85% cynical most of the time ...

I have no way of evaluating the position of RFK-jr in the pantheon of truthsayers. However if only ONE thing is true in that massive collection of alarming ideas namely that Dr Fauci and the other movers and groovers in his organisation who are responsible for research funds and government recommendations and policies, are allowed to profit from some of the patents on the drugs and treatments they are recommending ---- how obviously corrupt is that??????

Passthecream said...

This is a tangent to a more mainstream report than the RFK book and not the least bit surprising.